National Center for
4IRZ: Crystal Structure of A4b7 Headpiece Complexed With FAB Natalizumab
J. Biol. Chem. (2013) 288 p.32314-32325
Natalizumab antibody to alpha4-integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an alpha4 integrin beta-propeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the circumference of the beta-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the beta-subunit betaI domain and shows no difference in structure when bound to Fab. Competition between Fab and the ligand vascular cell adhesion molecule (VCAM) for binding to cell surface alpha4beta1 shows noncompetitive antagonism. In agreement, VCAM docking models suggest that binding of domain 1 of VCAM to alpha4-integrins is unimpeded by the Fab, and that bound Fab requires a change in orientation between domains 1 and 2 of VCAM for binding to alpha4beta1. Mapping of species-specific differences onto alpha4beta1 and alpha4beta7 shows that their ligand-binding sites are highly conserved. Skewing away from these conserved regions of the epitopes recognized by current therapeutic function-blocking antibodies has resulted in previously unanticipated mechanisms of action.